This proposal describes a 5-year research and training program designed to investigate how the vascular endothelium senses the local hemodynamic environment and mediates an adaptive or pathologic response. Clinical studies show that atherosclerotic lesions tend to develop in regions of the vasculature exposed to turbulent (low shear) blood flow. Regions of high shear tend to be protected. Elucidating how local hemodynamic conditions effect vascular biological responses may lead to important advances in the treatment and prevention of vascular diseases, such as, atherosclerosis. The central hypothesis of this proposal is that a recently discovered shear-responsive transcription factor, LKLF, plays a critical role in modulating the vascular response to hemodynamic shear. The specific aims outlined in this proposal will test this hypothesis by (1) confirming the shear-responsiveness of LKLF ex vivo and identifying shear-responsive elements in the LKLF promoter, (2) determining if LKLF is similarly regulated by hemodynamic shear in vivo, and (3) determining if loss of LKLF in murine adult vasculature causes loss of normal vascular function and increases susceptibility to and severity of atherosclerosis. This research plan is also designed to provide the candidate with outstanding research training and mentorship during transition to a career of independent investigation as a physician-scientist. The training program will be supervised by Mark L. Kahn, M.D., in the Molecular Cardiology Research Center (MCRC) at the University of Pennsylvania. Dr. Kahn is an internationally recognized expert in vascular development and pathobiology. The MCRC, co-directed by Jonathon A. Epstein, M.D., and Michael S. Parmacek, M.D., Division Chief, offers extensive collaborative opportunities, core facilities, and intellectual expertise in nearly all aspects of vascular biology. Atherosclerosis studies will be performed in collaboration with Daniel S. Rader, M.D., an international leader in the field of lipid biology and pathogenesis of atherosclerosis.